CA1128946A - Process for preparing piperidyl-indole derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of piperidyl-indole derivatives as well as their addition salts with pharmaceutically acceptable mineral or organic acids, derivatives corresponding to formula I: I in which X represents a hydrogen atom, fluorine, chlorine, bromine, an alkoxy radical containing 1 to 3 carbon atoms or a nitro radical and R represents a hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms, characterized in that the reacting a product of general formula II: II in which X and R are defined as above, with 4-piperidone hydrochloride in an alkaline medium, to obtain the desired product of formula I, which is isolated in the base form and, if necessary, salify the latter. The compounds obtained according to the invention are endowed with antidepressant, antiparkinsonnian and antiemetic properties.

Description

4 ~ i `

The present invention relates to a new process for the preparation of piperidyl-indol.e derivatives as well as their addition salts with mineral or organic acids pharmaceutically acceptable, derivatives corresponding to the formula H

H

in which X represents a hydrogen, fluorine atom, chlorine, bromine, an alkoxy radical containing from 1 to 3 carbon atoms or a nitro radical and R represents an atom of hydrogen or an alkyl radical containing 1 to 3 atoms of carbon.
In formula I and in the following, the substituent X can be in position 5 or in position 6 of the indole; the alkoxy radical containing 1 to 3 carbon atoms denotes, for example, a methoxy, ethoxy or propoxy radlcal and the alkyl radical containing 1 to 3 carbon atoms may denote a methyl, ethyl, propyl or isopropyl radical.
Addition salts with mineral acids or pharmaceutically acceptable organic can be, for example example, the salts formed with hydrochloric acids, hydrobromic! hydroiodic, nitric, sulfuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesul: Eonic, such as methane and ethane acids sulfonic, arylsulfonic, such as benzene accles and sulfonic and arylcarboxylic paratoluene.
The process for preparing the derivatives of Eormule I, object of the invention, is characterized in that one makes react a product of general formula II:

~ z ~

~ R II

in which X and R are defined as above, with the 4-piperidone hydrochloride in an alkaline medium, to obtain the sought product of formula I, which is isolated in the form of base and, if necessary, salify the latter.
In pre ~ erential conditions the execution of the invention, the process described above is characterized in that -10 a) the alkaline medium consists of 2N methanolic potassium hydroxide, but it is also possible to use sodium hydroxide or an alkaline alcoholate;
b) the reaction is carried out at reflux of the reaction mixture.
The addition salts of the derivatives of formula I can be prepared by reacting, in appreciable proportions stoichiometric, a mineral or organic acid with said derivatives.
Among ~ es products of formula I, some are described in French patent 2,362,628. Other products of formula I are new. Among these, mention may be made of 5-nitro 3- (1,2,3,6-tetrah ~ dropyridin-4-yl) lH-indole and its addition salts with mineral or organic pharma acids ceutically acceptable.
-Like the French patent products 2,362,628 mentioned above, 5-nitro 3- (1,2,3,6-tetrahydropyridin-4-yl ~ 1H-indole and its addition salts pharmaceutically acceptable, have very interesting pharmaceutical properties ecological; they are gifted, in particular, with certain properties antidepressants, antiparkinsonniennes and antiemetics.
These properties are illustrated later in the 3 ~ experimental part.
These properties justify the use of 5-nitro 3-(1,2,3,6-tetrahydropyridin-4-yl) 1H-indole and its salts of pharmaceutically acceptable addition, as medicaments.
These drugs find, for example, their use in the treatment of mental disorders, behavior, character disorders, in treatment akinetic and dyskinetic states as well as in the treatment of vomiting and nausea of all origins.
The usual dose, which varies depending on the product used, the subject treated and the affection in question, can be, for example, 5 mg to 500 mg daily, orally in humans.
5-nitro 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole and its addition salts with pharmaceutical acids can be used to prepare pharmaceutical compositions comprising said compound or at least one of its salts, as an active principle.
As drugs, 5-nitro 3- (1,2,3,6-tetrahy-dropyridin- ~ -yl) 1H-indole and its addition salts with pharmaceutically acceptable acids can be incorporated in pharmaceutical compositions intended for the route digestive or parenteral.
These pharmaceutical compositions can be, for example example, solid or liquid and come in the forms pharmaceutical commonly used in human medicine, such as, for example, simple or coated tablets, capsules, capsules, granules, suppositories, injections; they are prepared according to usual methods. The active ingredient (s) can be there incorporated into excipients usually used in these pharmaceutical compositions, such as talc, macaw gum ~ i-that, lactose, starch, magnesium stearate, butter cocoa, aqueous vehicles or not, original fatty substances animal or vegetable, paraffinic derivatives, glycols, the various wetting agents, dispersants or emulsifiers, conservatives.
It will now be given, without limitation, examples of implementation of the invention.
EXAMPLE 1 Neutral fumarate of 6-methoxy 3- (1,2,3,6-tetrahydro-pyridin-4-yl) 1H-indole.
- The mixture is brought to reflux under an inert atmosphere 20 g of 6-methoxy 1H-indole with 41.75 g of hydrochloride hydrate of 4-piperidone in 205 cm3 of methanolic potassium for 8:30 a.m., slowly dilute with water to 1.2 liters, crystallize, stir 30 minutes, rinse with water, dry under vacuum at 50 ° C
presence of desiccant and obtains 23.05 g of the base of the product sought.
Pre ~ aration of fumarate:
10 g of the base obtained are dissolved in 300 cm3 of methanol at 50C, filter, add 2.5 g of eumaric acid, crystallizes, shakes for 3 hours in the dark, filter under reduced pressure, rinse with methols, dry under vacuum at 50C, collects 9.3 g of crude product which is redissolved in 300 cm3 of distilled water, filter hot and then cool to initiate crystallization. After 2 hours of temperate rest rature, filter, rinse with water, dry under vacuum at 50C in the presence of a desiccant and obtains 6.3 g of the product - expected melting at 257-260C.
Analysis: C32H36N46 calculated C% = 67.11 H% = 6.33 N% = 9.78 found 67.2 6.4 9.9 EXAMPLE 2: 5-chloro 3- ~ lr2 ~ 3 ~ 6-tetrahydropyridin-4-yl ~ lH-indole.
.
15.1 g are brought to reElux under an inert atmosphere 5-chloro 1H-indole with 30.7 g hydrochloride hydrate of 4-piperidone and 150 cm3 of 2 N methanolic potassium for 7:30 a.m., leave overnight at room temperature, pour into 1.5 , liter of water, extract with ethyl acetate, wash with water and ~
salt water, dry over magnesium sulfate and evaporate to dryness.
The 20.5 g are redissolved at reflux in I 1 of benzene of crude product obtained, hot filter, leaves to crystallize, after 3 hours wring, rinse with benzene and obtain 10.2 g of sought product melting at 177C, then 2.49 g melting at 175-177C
by concentration of the mother liquors and crystallization, i.e.
in total 12.69 g of the sought product.
Analysis after purification by salification then return to 10 base:
F = 177-179C

C13H13ClN2 ~ 232.72 Calculated: Ç ~ = 67.09 H% = 5.63 Cl ~ = 15.23 N ~ = 12.03 Found: 67.4 5.8 15ll 11.7 EX MPLE 3: 5-methox ~ 3- (1! 2,3,6 tetrahydropyridin-4-yl) 1H-indole.
14.7 g of reElux are brought to an inert atmosphere 5-methoxy 1H-indole with 30.7 g of 4-piperidone hydrochloride monohydrate in 150 cm3 of 2 H methanolic potassium for 8:30 am After cooling, 300 cm3 of water are added, crystallizes, cools to 10C, filters, pastes 3 times with water,

2 times with ethanol, 2 times with ether, dried under pressure reduced to 20C and obtains 18.25 g of the sought product SOU5 form a light yellow powder melting at 183C.
EXAMPLE 4 5-nitro 3- hydrochloride (1,2,3,6 tetrah ~ dro-~ idin-4 ~ 1H-indole.
The procedure is analogous to that described in the examples 1, 2 or 3, starting from 0.8 g of 5-nitro l ~ -indole and 1.53 g of chlorh hydrate ~ 4-piperidone drate in 16 cm3 of 2N methanolic potash.
0.86 g of crude product is obtained, which is recrystallized from - is in isopropanol. 0.74 g of expected product is obtained.

:

~ 1 ~ .8 ~

F. = 250C.
Preparation of the hydrochloride The hydrochloride of the product obtained is prepared below.

above, in ethyl acetate by addition of a solution saturated with hydrochloric acid in ethyl acetate.
After recrystallization from methanol, aqueous the expected pure product melting at 275C.
Analysis: CH ClN 0 = 279.733 Calculated: C% 55.82 H ~ 5.04 Cl% 12.68 N% 15.02 Found: 56.0 5.1 12.8 14.8 EXAMPLE 5 Pharmaceutical composition:
We prepa ~ ed tablets corresponding to the formula:
- 5-nitro 3- hydrochloride (1,2l3,6-tetrah ~ dropyridin-4-yl) lH-indole ....................................... 25 ml - Excipient qs for a tablet finished at ............ 200 mg (detail of the excipient: talc, starch, stearate magnesium).
EXAMPLE 6 ~ pharmaceutical position ~ ue:
An injectable solution has been prepared that meets the formula :
- 5 nltro 3- hydrochloride (1,2,3,6-tetrahydropyridin-4-yl) 1 H-indole ~ 25 mg - Sterile aqueous excipient qs ...................... 2 ml Pharmacological study.
1) ~ otentialisation test of stereoty ~ ies with am ~ hetamine:
____ ___ _ _______ _______ _________ __________ __ ~ ____ The tests are carried out on batches of 5 rats males from 150 to IB0 g. Each animal is placed individually in a wire cage (29 x 25 x 17 cm) containing some wood crumbling debris.
A one hour delay is observed between the administration tion of the compound studied and the injection of 5 mg / kg of sulfate dexamphetamine.

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The behavior of anima ~ x is then noted all 1/2 hour for 5 hours with the recommended rating by HALLIWELL et Coll. (Brit. J. Pharmacol. 1964, 23, 330-350).
The animal is asleep (O), it is awake but stationary (1), it turns in the cage (2), it sniffs the '' cover (3), it licks the walls (4), it touches the chips or the bars of the cage with the teeth (5), it bites the shavings or the bars of the cage (6).
The intensity of stereotypies is expressed under the form of a score between O and 30 corresponding to the sum of the values obtained on the 5 rats of a batch at each time. The sum of the scores recorded in 5 hours is calculated.
The compounds are administered intraper-toneale.
The dose of compound which increases by about 100%
the sum of the scores in 5 hours is 20 mg ~ kg for the compound from example 4 2) Anta ~ onism test vis-à-vis the catale ~ sie à la rochlor-___________ _ ___________________________ _________ _________ ~ érazlne:
, The tests are carried out on batches of 5 male rats about 100 g.
The test compound is administered intraper-tonal simultaneously with. a dose of 15 mg / kg of prochlor-perazine intraperitoneally.
Catalepsy is appreciated every hour during 7 hours following the cross-legged homolateral test (BOISSIER, SIMON, ~ h therapy, 1963, 18, 1257-1277) with the following rating:
- The animal re ~ uses the crossing of the forelegs with the homolateral hind legs (O), it accepts the crossing sought only on one side (0.5), it accepts the crossing on both sides (1).

.

The compound of example 4 is opposed to catalepsy induced by prochlorperzilne at a dose of 1 mg / kg.

- 3) Study of the toxicity ai uë ~
_. g Acute toxicity is determined on lots of ten mice weighing approximately 20 g which are administered increasing doses of the compound intraperitoneally studied ~
Mortality is noted 48 hours after administration.
tration of the compound.
The approximate LD50 of the compound of Example 4 is equal to 165 mg / kg.

Claims (5)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of piperidyl derivatives indole as well as their addition salts with acids pharmaceutically acceptable minerals or organics, derivatives corresponding to formula I:

I

in which X represents a hydrogen or fluorine atom, chlorine, bromine, an alkoxy radical containing from 1 to 3 carbon atoms or a nitro radical and R represents a hydrogen atom or an alkyl radical containing from 1 to 3 carbon atoms, characterized in that one reacts a product of general formula II;

in which X and R are defined as above, with the 4-piperidone hydrochloride in an alkaline medium, to obtain the product of formula I sought, which is isolated in the form base and, if necessary, salify the latter. 2. Method according to claim 1, characterized in that the alkaline medium consists of potash methanolic 2N. 3. Method according to claim 1 or 2, characterized in that the reaction at reflux of the mixture is carried out reactive. 4. Method according to claim 1, characterized in that a product of formula II is used at the start in which X in position 5 represents a nitro radical and R
represents a hydrogen atom. 5. 5-nitro 3- (1,2,3,6-tetrahydropyridin-4-yl) 1H-indole and its addition salts with mineral acids or pharmaceutically acceptable organic, whenever are obtained by a process according to claim 4 or its manifest chemical equivalents.